Method for preparing intermediates useful in synthesis of retroviral protease inhibitors

ABSTRACT

A synthesis is described for intermediates which are readily amenable to the large scale preparation of hydroxyethylurea-based chiral HIV protease inhibitors. The method includes forming a diastereoselective epoxide from a chiral alpha amino aldehyde.

[0001] This application is a continuation in part of U.S. patentapplication Ser. No. 07/886,558, filed May 20, 1992, which is acontinuation in part of PCT/US91/8613, filed Nov. 18, 1991, which is acontinuation in part of Ser. No. 07/789,646, filed Nov. 14, 1991, whichis a continuation in part of U.S. patent application Ser. No.07/615,210, filed Nov. 19, 1990.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] Synthesis of many HIV protease inhibitors containing ahydroxyethylamine or hydroxyethylurea isostere include the amine openingof a key intermediate chiral epoxide. The synthesis of the key chiralepoxide requires a multi-step synthesis starting from L-phenylalanineand results in a low overall yield. The diastereoselectivity of thereduction step of the intermediate amino chloromethylketone is low anduse of explosive diazomethane prevents the scale up of the method tomultikilogram productions. The present invention relates to a method ofpreparing retroviral protease inhibitors and more particularly to adiastereoselective method of forming chiral intermediates for thepreparation of urea containing hydroxyethylamine protease inhibitors.

[0004] 2. Related Art

[0005] Roberts et al, Science, 248, 358 (1990), Krohn et al, J. Med.Chem. 344, 3340 (1991) and Getman, et al, J. Med. Chem., 346, 288 (1993)have previously reported synthesis of protease inhibitors containing thehydroxyethylamine or hydroxyethylurea isostere which include the openingof an epoxide generated in a multi-step synthesis starting from an aminoacid. These methods also contain steps which include diazomethane andthe reduction of an amino chloromethyl ketone intermediate to an aminoalcohol prior to formation of the epoxide. The overall yield of thesesyntheses are low and the use of explosive diazomethane additionallyprevents such methods from being commercially acceptable.

[0006] Tinker et al U.S. Pat. No. 4,268,688 discloses a catalyticprocess for the asymmetric hydroformylation to prepare optically activealdehydes from unsaturated olefins. Similarly, Reetz et al U.S. Pat. No.4,990,669 discloses the formation of optically active alpha aminoaldehydes through the reduction of alpha amino carboxylic acids or theiresters with lithium aluminum hydride followed by oxidation of theresulting protected beta amino alcohol by dimethyl sulfoxide/oxalylchloride or chromium trioxide/pyridine. Alternatively, protected alphaamino carboxylic acids or esters thereof can be reduced withdiisobutylaluminum hydride to form the protected amino aldehydes.

[0007] Reetz et al (Tet. Lett., 30, 5425 (1989) disclosed the use ofsulfonium and arsonium ylides and their reactions of protected α-aminoaldehydes to form aminoalkyl epoxides. This method suffers from the useof highly toxic arsonium compounds or the use of combination of sodiumhydride and dimethyl sulfoxide which is extremely hazardous in largescale. (Sodium hydride and DMSO are incompatible: Sax, N. I., “DangerousProperties of Industrial Materials”, 6th Ed., Van Nostrand Reinhold Co.,1984, p. 433. Violent explosions have been reported on the reaction ofsodium hydride and excess DMSO, “Handbook of Reactive Chemical Hazards”,3rd Ed., Butterworths, 1985, p. 295. Matteson et al Synlett., 1991, 631reported the addition of chloromethylithium or bromomethylithium toracemic aldehydes.

[0008] Tet.Letters, Vol. 27, No. 7, 1986, pages 795-798 discloses ingeneral the oxidation of carbonyl compounds to epoxides orchlorohydrines using chloro- or bromomethyllithium. The referencehowever is silent about amino aldehydes as well as optically activecompounds.

SUMMARY OF THE INVENTION

[0009] Human immunodeficiency virus (HIV), the causative agent ofacquired immunodeficiency syndrome (AIDS), encodes three enzymes,including the well-characterized proteinase belonging to the asparticproteinase family, the HIV protease. Inhibition of this enzyme isregarded as a promising approach for treating AIDS. One potentialstrategy for inhibitor design involves the introduction ofhydroxyethylene transition-state analogs into inhibitors. Inhibitorsadapting the hydroxyethylamine or hydroxyethylurea isostere are found tobe highly potent inhibitors of HIV proteases. Despite the potentialclinical importance of these compounds, previously there were nosatisfactory synthesis which could be readily and safely scaled up toprepare large kilogram quantities of such inhibitors needed fordevelopment and clinical studies. This invention provides an efficientsynthesis of intermediates which are readily amenable to the large scalepreparation or hyrdoxyethylurea-based chiral HIV protease inhibitors.

[0010] Specifically, the method includes preparing a diastereoselectiveepoxide from a chiral alpha amino aldehyde.

DETAILED DESCRIPTION OF THE INVENTION

[0011] This invention relates to a method of preparation of HIV proteaseinhibitor that allows the preparation of commercial quantities ofintermediates of the formula

[0012] wherein R¹ is selected from alkyl, aryl, cycloalkyl,cycloalkylalkyl and arylalkyl, which are optionally substituted with agroup selected from alkyl, halogen, NO₂, OR⁹ or SR⁹, where R⁹ representshydrogen or alkyl; and P¹ and P² independently are selected from amineprotecting groups, including but not limited to, arylalkyl, substitutedarylalkyl, cycloalkenylalkyl and substituted cycloalkenylalkyl, allyl,substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl and silyl.Examples of arylalkyl include, but are not limited to benzyl,ortho-methylbenzyl, trityl and benzhydryl, which can be optionallysubstituted with halogen, alkyl of C₁-C₈, alkoxy, hydroxy, nitro,alkylene, amino, alkylamino, acylamino and acyl, or their salts, such asphosphonium and ammonium salts. Examples of aryl groups include phenyl,naphthalenyl, indanyl, anthracenyl, durenyl, 9-(9-phenylfluorenyl) andphenanthrenyl, cycloalkenylalkyl or substituted cycloalkylenylalkylradicals containing cycloalkyls of C₆-C₁₀. Suitable acyl groups includecarbobenzoxy, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substitutedbenzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloroacetyl, phthaloyland the like.

[0013] Additionally, the P¹ and/or P² protecting groups can form aheterocyclic ring with the nitrogen to which they are attached, forexample, 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl,maleimidyl and the like and where these heterocyclic groups can furtherinclude adjoining aryl and cycloalkyl rings. In addition, theheterocyclic groups can be mono-, di- or tri-substituted, e.g.,nitrophthalimidyl. The term silyl refers to a silicon atom optionallysubstituted by one or more alkyl, aryl and aralkyl groups.

[0014] Suitable silyl protecting groups include, but are not limited to,trimethylsilyl, triethylsilyl, tri-isopropylsilyl,tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of the amine functions to provide mono-or bis-disilylamine can provide derivatives of the aminoalcohol, aminoacid, amino acid esters and amino acid amide. In the case of aminoacids, amino acid esters and amino acid amides, reduction of thecarbonyl function provides the required mono- or bis-silyl aminoalcohol.Silylation of the aminoalcohol can lead to the N,N,O-tri-silylderivative. Removal of the silyl function from the silyl ether functionis readily accomplished by treatment with, for example, a metalhydroxide or ammonium flouride reagent, either as a discrete reactionstep or in situ during the preparation of the amino aldehyde reagent.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-buty-dimethylsilyl chloride, phenyldimethylsilyl chlorie,diphenylmethylsilyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

[0015] Preferably P¹, P² and R¹ are independently selected from aralkyland substituted aralkyl. More preferably, each of P¹, P² and R¹ isbenzyl.

[0016] Protected alpha-aminoaldehyde intermediates of the formula:

[0017] and protected chiral alpha-amino alcohols of the formula:

[0018] wherein P¹, P² and R¹ are as defined above, are also describedherein.

[0019] As utilized herein, the term “amino epoxide” alone or incombination, means an amino-substituted alkyl epoxide wherein the aminogroup can be a primary, or secondary amino group containing substituentsselected from hydrogen, and alkyl, aryl, aralkyl, alkenyl,alkoxycarbonyl, aralkoxycarbonyl, cycloalkenyl, silyl, cycloalkylalkenylradicals and the like and the epoxide can be alpha to the amine. Theterm “amino aldehyde” alone or in combination, means anamino-substituted alkyl aldehyde wherein the amino group can be aprimary, or secondary amino group containing substituents selected fromhydrogen, and alkyl, aryl, aralkyl, alkenyl, aralkoxycarbonyl,alkoxycarbonyl, cycloalkenyl, silyl, cycloalkylalkenyl radicals and thelike and the aldehyde can be alpha to the amine. The term “alkyl”, aloneor in combination, means a straight-chain or branched-chain alkylradical containing from 1 to about 10, preferably from 1 to about 8,carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, octyl and the like. The term “alkenyl”, alone or in combination,means a straight-chain or branched-chain hydrocarbon radial having oneor more double bonds and containing from 2 to about 18 carbon atomspreferably from 2 to about 8 carbon atoms. Examples of suitable alkenylradicals include ethenyl, propenyl, allyl, 1,4-butadienyl and the like.The term “alkoxy”, alone or in combination, means an alkyl ether radicalwherein the term alkyl is as defined above. Examples of suitable alkylether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy and the like. The term“cycloalkenyl”, alone or in combination, means an alkyl radical whichcontains from about 3 to about 8 carbon atoms and is cyclic and whichcontains at least one double bond in the ring which is non-aromatic incharacter. The term “cycloalkenylalkyl” means cycloalkenyl radical asdefined above which is attached to an alkyl radical, the cyclic portioncontaining from 3 to about 8, preferably from 3 to about 6, carbonatoms. Examples of such cycloalkyl radicals include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of suchcycloalkenyl radicals include cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, dihydrophenyl and the like. The term“aryl”, alone or in combination, means a carbocyclic aromatic systemcontaining one, two or three rings wherein such rings may be attachedtogether in a pendent manner or may be fused. Examples of “aryl” includephenyl or naphthyl radical either of which optionally carries one ormore substituents selected from alkyl, alkoxy, halogen, hydroxy, amino,nitro and the like, as well as p-tolyl, 4-methoxyphenyl,4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl,1-naphthyl, 2-naphthyl, and the like. The term “aralkyl”, alone or incombination, means an alkyl radical as defined above in which onehydrogen atom is replaced by an aryl radical as defined above, such asbenzyl, 2-phenylethyl and the like. Examples of substituted aralkylinclude 3,5-dimethoxybenzyl bromide, 3,4-dimethoxybenzyl bromide,2,4-dimethoxybenzyl bromide, 3,4,5-trimethoxybenzyl bromide,4-nitrobenzyl iodide, 2,6-dichlorobenzyl bromide,1,4-bis(chloromethyl)benzene, 1,2-bis(bromomethyl)benzene,1,3-bis(chloromethyl)-benzene, 4-chlorobenzyl chloride, 3-chlorobenzylchloride, 1,2-bis(chloromethyl)benzene, 6-chloropiperonyl chloride,2-chlorobenzyl chloride, 4-chloro-2-nitrobenzyl chloride,2-chloro-6-fluorobenzyl chloride,1,2-bis(chloromethyl)-4,5-dimethylbenzene, 3,6-bis(chloromethyl)durene,9,10-bis(chloromethyl)anthracene, 2,5-bis(chloromethyl)-p-xylene,2,5-bis(chloromethyl)-1,4-dimethoxybenzene,2,4-bis(chloromethyl)anisole, 4,6-(dichloromethyl)-m-xylene,2,4-bis(chloromethyl)mesitylene,4-(bromomethyl)-3,5-dichlorobenzophenone,n-(alpha-chloro-o-tolyl)-benzylamine hydrochloride,3-(chloromethyl)benzoyl chloride, 2-chloro-4-chloromethyltoluene,3,4-dichlorobenzyl bromide, 6-chloro-8-chloromethylbenzo-1,3-dioxan,4-(2,6-dichlorobenzylsulphonyl)benzylbromide,5-(4-chloromethylphenyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole,5-(3-chloromethylphenyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole,4-(chloromethyl)benzoyl chloride, di(chloromethyl)toluene,4-chloro-3-nitrobenzyl chloride,1-(dimethylchlorosilyl)-2-(p,m-chloromethylphenyl)ethane,1-(dimethylchlorosilyl)-2-(p,m-chloromethylphenyl)ethane,3-chloro-4-methoxybenzyl chloride, 2,6-bis(chloromethyl)-4-methylphenol,2,6-bis(chloromethyl)-p-tolyl acetate, 4-bromobenzyl bromide,p-bromobenzoyl bromide, alpha alpha,-dibromo-m-xylene, 3-bromobenzylbromide, 2-bromobenzyl bromide, 1,8-bis(bromomethyl)naphthalene,o-xylylene dibromide, p-xylylene dibromide,2,2′-bis(bromomethyl)-1,1′-biphenyl,alpha,alpha′-dibromo-2,5-dimethoxy-p-xylene, benzyl chloride, benzylbromide, 4,5-bis(bromomethyl)phenanthrene,3-(bromomethyl)benzyltriphenylphosphonium bromide,4-(bromomethyl)benzyltriphenylphosphonium bromide,2-(bromomethyl)benzyltriphenylphosphonium bromide,1-(2-bromoethyl)-2-(bromomethyl)-4-nitrobenzene,2-bromo-5-fluorobenzylbromide, 2,6-bis(bromomethyl) fluorobenzene,o-bromomethylbenzoyl bromide, p-bromomethyl benzoyl bromide,1-bromo-2-(bromomethyl)naphthalene, 2-bromo-5-methoxybenzyl bromide,2,4-dichlorobenzyl chloride, 3,4-dichlorobenzyl chloride,2,6-dichlorobenzyl chloride, 2,3-dichlorobenzyl chloride,2,5-dichlorobenzyl chloride,methyldichlorosilyl(chloromethylphenyl)ethane,methyldichlorosilyl(chloromethylphenyl)ethane,methyldichlorosilyl(chloromethylphenyl)ethane, 3,5-dichlorobenzylchloride, 3,5-dibromo-2-hydroxybenzyl bromide, 3,5-dibromobenzylbromide, p-(chloromethyl)phenyltrichlorosilane,1-trichlorosilyl-2-(p,m-chloromethylphenyl)ethane, 1-trichlorosilyl-2-(p,m-chloromethylphenyl)ethane, 1,2,4,5-tetrakis(bromomethyl)benzene.The term aralkoxycarbonyl means an aralkoxyl group attached to acarbonyl. Carbobenzoxy is an example of aralkoxycarbonyl. The term“heterocyclic ring system” means a saturated or partially unsaturatedmonocyclic, bicyclic or tricyclic heterocycle which contains one or morehetero atoms as ring atoms, selected from nitrogen, oxygen, silicon andsulphur, which is optionally substituted on one or more carbon atoms byhalogen, alkyl, alkoxy, oxo, and the like, and/or on a secondarynitrogen atom (i.e., —NH—) by alkyl, aralkoxycarbonyl, alkanoyl, phenylor phenylalkyl or on a tertiary nitrogen atom (i.e. ═N—) by oxido andwhich is attached via a carbon atom. Examples of such heterocyclicgroups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiamorpholinyl, pyrrolyl, phthalimide, succinimide, maleimide, and thelike. Also included are heterocycles containing two silicon atomssimultaneously attached to the nitrogen and joined by carbon atoms. Theterm “alkylamino” alone or in combination, means an amino-substitutedalkyl group wherein the amino group can be a primary, or secondary aminogroup containing substituents selected from hydrogen, and alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like. The term“halogen” means fluorine, chlorine, bromine or iodine. The termdihaloalkyl means two halogen atoms, the same or different, substitutedon the same carbon atom. The term “oxidizing agent” includes a singleagent or a mixture of oxidizing reagents. Examples of mixtures ofoxidizing reagents include sulfur trioxide-pyridine/dimethylsulfoxide,oxalyl chloride/dimethyl sulfoxide, acetyl chloride/dimethyl sulfoxide,acetyl anhydride/dimethyl sulfoxide, trifluoroacetyl chloride/dimethylsulfoxide, toluenesulfonyl bromide/dimethyl sulfoxide, phosphorouspentachloride/dimethyl sulfoxide and isobutylchloroformate/dimethylsulfoxide.

[0020] A general Scheme for the preparation of amino epoxides, useful asintermediates in the synthesis of HIV protease inhibitors is shown inScheme 1 below.

[0021] The economical and safe large scale method of preparation ofprotease inhibitors of the present invention can alternatively utilizeamino acids or amino alcohols to form N,N-protected alpha aminoalcoholof the formula

[0022] wherein P¹, P² and R¹ are described above.

[0023] Whether the compounds of Formula II are formed from amino acidsor aminoalcohols, such compounds have the amine protected with groups P¹and P² as previously identified. The nitrogen atom can be alkylated suchas by the addition of suitable alkylating agents in an appropriatesolvent in the presence of base.

[0024] Alternate bases used in alkylation include sodium hydroxide,sodium bicarbonate, potassium hydroxide, lithium hydroxide, potassiumcarbonate, sodium carbonate, cesium hydroxide, magnesium hydroxide,calcium hydroxide or calcium oxide, or tertiary amine bases such astriethyl amine, diisopropylethylamine, N-methylpiperidine, pyridine,dimethylaminopyridine and azabicyclononane. Reactions can be homogenousor heterogenous. Suitable solvents are water and protic solvents orsolvents miscible with water, such as methanol, ethanol, isopropylalcohol, tetrahydrofuran and the like, with or without added water.Dipolar aprotic solvents may also be used with or without added proticsolvents including water. Examples of dipolar aprotic solvents includeacetonitrile, dimethylformamide, dimethyl acetamide, acetamide,tetramethyl urea and its cyclic analog, dimethylsulfoxide,N-methylpyrrolidone, sulfolane, nitromethane and the like. Reactiontemperature can range between about −20° to 100° C. with the preferredtemperature of about 25-85° C. The reaction may be carried out under aninert atmosphere such as nitrogen or argon, or normal or dry air, underatmospheric pressure or in a sealed reaction vessel under positivepressure. The most preferred alkylating agents are benzyl bromide orbenzyl chloride or monosubstituted aralkyl halides or polysubstitutedaralkyl halides. Sulfate or sulfonate esters are also suitable reagentsto provide the corresponding benzyl analogs and they can be preformedfrom the corresponding benzyl alcohol or formed in situ by methods wellknown to those skilled in the art. Trityl, benzhydryl, substitutedtrityl and substituted benzhydryl groups, independently, are alsoeffective amine protecting groups [P¹,P²] as are allyl and substitutedallyl groups. Their halide derivatives can also be prepared from thecorresponding alcohols by methods well known to those skilled in the artsuch as treatment with thionyl chloride or bromide or with phosphorustri- or pentachloride, bromide or iodide or the corresponding phosphoryltrihalide. Examples of groups that can be substituted on the aryl ringinclude alkyl, alkoxy, hydroxy, nitro, halo and alkylene, amino, mono-and dialkyl amino and acyl amino, acyl and water solubilizing groupssuch as phosphonium salts and ammonium salts. The aryl ring can bederived from, for example, benzene, napthelene, indane, anthracene,9-(9-phenyl fluorenyl, durene, phenanthrene and the like. In addition,1,2-bis (substituted alkylene) aryl halides or sulfonate esters can beused to form a nitrogen containing aryl or non-aromatic heterocyclicderivative [with P¹ and P²] or bis-heterocycles. Cycloalkylenealkyl orsubstituted cyloalkylene radicals containing 6-10 carbon atoms andalkylene radicals constitute additional acceptable class of substituentson nitrogen prepared as outlined above including, for example,cyclohexylenemethylene.

[0025] Compounds of Formula II can also be prepared by reductivealkylation by, for example, compounds and intermediates formed from theaddition of an aldehyde with the amine and a reducing agent, reductionof a Schiff Base, carbinolamine or enamine or reduction of an acylatedamine derivative. Reducing agents include metals [platinum, palladium,palladium hydroxide, palladium on carbon, platinum oxide, rhodium andthe like] with hydrogen gas or hydrogen transfer molecules such ascyclohexene or cyclohexadiene or hydride agents such as lithiumaluminumhydride, sodium borohydride, lithium borohydride, sodiumcyanoborohydride, diisobutylaluminum hydride or lithiumtri-tert-butoxyaluminum hydride.

[0026] Additives such as sodium or potassium bromide, sodium orpotassium iodide can catalyze or accelerate the rate of aminealkylation, especially when benzyl chloride was used as the nitrogenalkylating agent.

[0027] Phase transfer catalysis wherein the amine to be protected andthe nitrogen alkylating agent are reacted with base in a solvent mixturein the presence of a phase transfer reagent, catalyst or promoter. Themixture can consist of, for example, toluene, benzene, ethylenedichloride, cyclohexane, methylene chloride or the like with water or aaqueous solution of an organic water miscible solvent such as THF.Examples of phase transfer catalysts or reagents includetetrabutylammonium chloride or iodide or bromide, tetrabutylammoniumhydroxide, tri-butyloctylammonium chloride, dodecyltrihexylammoniumhydroxide, methyltrihexylammonium chloride and the like.

[0028] A preferred method of forming substituted amines involves theaqueous addition of about 3 moles of organic halide to the amino acid orabout 2 moles to the aminoalcohol. In a more preferred method of forminga protected amino alcohol, about 2 moles of benzylhalide in a basicaqueous solution is utilized. In an even more preferred method, thealkylation occurs at 50° C. to 80° C. with potassium carbonate in water,ethanol/water or denatured ethanol/water. In a more preferred method offorming a protected amino acid ester, about 3 moles of benzylhalide isadded to a solution containing the amino acid.

[0029] The protected amino acid ester is additionally reduced to theprotected amino alcohol in an organic solvent. Preferred reducing agentsinclude lithium aluminiumhydride, lithium borohydride, sodiumborohydride, borane, lithium tri-ter-butoxyaluminum hydride, borane.HFcomplex. Most preferably, the reducing agent is diisobutylaluminumhydride (DiBAL-H) in toluene. These reduction conditions provide analternative to a lithium aluminum hydride reduction.

[0030] Purification by chromatography is possible. In the preferredpurification method the alpha amino alcohol can be purified by an acidquench of the reaction, such as with hydrochloric acid, and theresulting salt can be filtered off as a solid and the amino alcohol canbe liberated such as by acid/base extraction.

[0031] The protected alpha amino alcohol is oxidized to form a chiralamino aldehyde of the formula

[0032] Acceptable oxidizing reagents include, for example, sulfurtrioxide-pyridine complex and DMSO, oxalyl chloride and DMSO, acetylchloride or anhydride and DMSO, trifluoroacetyl chloride or anhydrideand DMSO, methanesulfonyl chloride and DMSO ortetrahydrothiaphene-S-oxide, toluenesulfonyl bromide and DMSO,trifluoromethanesulfonyl anhydride (triflic anhydride) and DMSO,phosphorus pentachloride and DMSO, dimethylphosphoryl chloride and DMSOand isobutylchloroformate and DMSO. The oxidation conditions reported byReetz et al [Agnew Chem., 99, p. 1186, (1987)], Agnew Chem. Int. Ed.Engl., 26, p. 1141, 1987) employed oxalyl chloride and DMSO at −78° C.

[0033] The preferred oxidation method described in this invention issulfur trioxide pyridine complex, triethylamine and DMSO at roomtemperature. This system provides excellent yields of the desired chiralprotected amino aldehyde usable without the need for purification i.e.,the need to purify kilograms of intermediates by chromatography iseliminated and large scale operations are made less hazardous. Reactionat room temperature also eliminated the need for the use of lowtemperature reactor which makes the process more suitable for commercialproduction.

[0034] The reaction may be carried out under and inert atmosphere suchas nitrogen or argon, or normal or dry air, under atmospheric pressureor in a sealed reaction vessel under positive pressure. Preferred is anitrogen atmosphere. Alternative amine bases include, for example,tri-butyl amine, tri-isopropyl amine, N-methylpiperidine, N-methylmorpholine, azabicyclononane, diisopropylethylamine,2,2,6,6-tetramethylpiperidine, N,N-dimethylaminopyridine, or mixtures ofthese bases. Triethylamine is a preferred base. Alternatives to pureDMSO as solvent include mixtures of DMSO with non-protic or halogenatedsolvents such as tetrahydrofuran, ethyl acetate, toluene, xylene,dichloromethane, ethylene dichloride and the like. Dipolar aproticco-solvents include acetonitrile, dimethylformamide, dimethylacetamide,acetamide, tetramethyl urea and its cyclic analog, N-methylpyrrolidone,sulfolane and the like. Rather than N,N-dibenzylphenylalaninol as thealdehyde precursor, the phenylalaninol derivatives discussed above canbe used to provide the corresponding N-monosubstituted [either P¹ orP²=H] or N,N-disubstituted aldehyde.

[0035] In addition, hydride reduction of an amide or ester derivative ofthe corresponding alkyl, benzyl or cycloalkenyl nitrogen protectedphenylalanine, substituted phenylalanine or cycloalkyl analog ofphenyalanine derivative can be carried out to provide a compound ofFormula III. Hydride transfer is an additional method of aldehydesynthesis under conditions where aldehyde condensations are avoided, cf,Oppenauer Oxidation.

[0036] The aldehydes of this process can also be prepared by methods ofreducing protected phenylalanine and phenylalanine analogs or theiramide or ester derivatives by, e.g., sodium amalgam with HCl in ethanolor lithium or sodium or potassium or calcium in ammonia. The reactiontemperature may be from about −20° C. to about 45° C., and preferablyfrom abut 5° C. to about 25° C. Two additional methods of obtaining thenitrogen protected aldehyde include oxidation of the correspondingalcohol with bleach in the presence of a catalytic amount of2,2,6,6-tetramethyl-1-pyridyloxy free radical. In a second method,oxidation of the alcohol to the aldehyde is accomplished by a catalyticamount of tetrapropylammonium perruthenate in the presence ofN-methylmorpholine-N-oxide.

[0037] Alternatively, an acid chloride derivative of a protectedphenylalanine or phenylalanine derivative as disclosed above can bereduced with hydrogen and a catalyst such as Pd on barium carbonate orbarium sulphate, with or without an additional catalyst moderating agentsuch as sulfur or a thiol (Rosenmund Reduction).

[0038] An important aspect of the present invention is a reactioninvolving the addition of chloromethylithium or bromomethyllithium tothe α-amino aldehyde. Although addition of chloromethyllithium orbromomethylithium to aldehydes is known, the addition of such species toracemic or chiral amino aldehydes to form aminoepoxides of the formula

[0039] is novel. The addition of chloromethylithium or bromomethylithiumto a chiral amino aldehyde is highly diastereoselective. Preferably, thechloromethyllithium or bromomethylithium is generated in-situ from thereaction of the dihalomethane and n-butyllithium. Acceptablemethyleneating halomethanes include chloroiodomethane,bromochloromethane, dibromomethane, diiodomethane, bromofluoromethaneand the like. The sulfonate ester of the addition product of, forexample, hydrogen bromide to formaldehyde is also a methyleneatingagent. Tetrahydrofuran is the preferred solvent, however alternativesolvents such as toluene, dimethoxyethane, ethylene dichloride,methylene chloride can be used as pure solvents or as a mixture. Dipolaraprotic solvents such as acetonitrile, DMF, N-methylpyrrolidone areuseful as solvents or as part of a solvent mixture. The reaction can becarried out under an inert atmosphere such as nitrogen or argon. Forn-butyl lithium can be substituted other organometalic reagents reagentssuch as methyllithium, tert-butyl lithium, sec-butyl lithium,phenyllithium, phenyl sodium and the like. The reaction can be carriedout at temperatures of between about −80° C. to 0° C. but preferablybetween about −80° C. to −20° C. The most preferred reactiontemperatures are between −40° C. to −15° C. Reagents can be added singlybut multiple additions are preferred in certain conditions. Thepreferred pressure of the reaction is atmospheric however a positivepressure is valuable under certain conditions such as a high humidityenvironment.

[0040] Alternative methods of conversion to the epoxides of thisinvention include substitution of other charged methylenation precurserspecies followed by their treatment with base to form the analogousanion. Examples of these species include trimethylsulfoxonium tosylateor triflate, tetramethylammonium halide, methyldiphenylsulfoxoniumhalide wherein halide is chloride, bromide or iodide.

[0041] The conversion of the aldehydes of this invention into theirepoxide derivative can also be carried out in multiple steps. Forexample, the addition of the anion of thioanisole prepared from, forexample, a butyl or aryl lithium reagent, to the protectedaminoaldehyde, oxidation of the resulting protected aminosulfide alcoholwith well known oxidizing agents such as hydrogen peroxide, tert-butylhypochlorite, bleach or sodium periodate to give a sulfoxide. Alkylationof the sulfoxide with, for example, methyl iodide or bromide, methyltosylate, methyl mesylate, methyl triflate, ethyl bromide, isopropylbromide, benzyl chloride or the like, in the presence of an organic orIinorganic base Alternatively, the protected aminosulfide alcohol can bealkylated with, for example, the alkylating agents above, to provide asulfonium salts that are subsequently converted into the subjectepoxides with tert-amine or mineral bases.

[0042] The desired epoxides form, using most preferred conditions,diastereoselectively in ratio amounts of at least about an 85:15 ratio(S:R). The product can be purified by chromatography to give thediastereomerically and enantiomerically pure product but it is moreconveniently used directly without purification to prepare HIV proteaseinhibitors.

[0043] This process is applicable to mixtures of optical isomers as wellas resolved compounds. If a particular optical isomer is desired, it canbe selected by the choice of starting material, e.g., L-phenylalanine,D-phenylalanine, L-phenylalaninol, D-phenylalaninol,D-hexahydrophenylalaninol and the like, or resolution can occur atintermediate or final steps. Chiral auxiliaries such as one or twoequivilants of camphor sulfonic acid, citric acid, camphoric acid,2-methoxyphenylacetic acid and the like can be used to form salts,esters or amides of the compounds of this invention. These compounds orderivatives can be crystallized or separated chromatographically usingeither a chiral or achiral column as is well known to those skilled inthe art.

[0044] A further advantage of the present process is that materials canbe carried through the above steps without purification of theintermedate products. However, if purification is desired, theintermediates disclosed can be prepared and stored in a pure state.

[0045] The practical and efficient synthesis described here has beensuccessfully scaled up to prepare large quantity of intermediates forthe preparation of HIV protease inhibitors. It offers several advantagesfor multikilogram preparations: (1) it does not require the use ofhazardous reagents such as diazomethane, (2) it requires no purificationby chromatography, (3) it is short and efficient, (4) it utilizesinexpensive and readily available commercial reagents, (5) it producesenantiomerically pure alpha amino epoxides. In particular, the processof the invention produces enantiomerically-pure epoxide as required forthe preparation of enantiomerically-pure intermediate for furthersynthesis of HIV protease inhibitors.

[0046] The amino epoxides were prepared utilizing the followingprocedure as disclosed in Scheme II below.

[0047] In Scheme II, there is shown a synthesis for the epoxide, chiralN,N,α-S-tris(phenylmethyl)-2S-oxiranemethan-amine. The synthesis startsfrom L-phenylalanine. The aldehyde is prepared in three steps fromL-phenylalanine or phenylalinol. L-Phenylalanine is converted to theN,N-dibenzylamino acid benzyl ester using benzyl bromide under aqueousconditions. The reduction of benzyl ester is carried out usingdiisobutylaluminum hydride (DIBAL-H) in toluene. Instead of purificationby chromatography, the product iss purified by an acid (hydrochloricacid) quench of the reaction, the hydrochloride salt is filtered off asa white solid and then liberated by an acid/base extraction. After onerecrystallization, chemically and optically pure alcohol is obtained.Alternately, and preferably, the alcohol can be obtained in one step in88% yield by the benzylation of L-phenylalaninol using benzylbromideunder aqueous conditions. The oxidation of alcohol to aldehyde is alsomodified to allow for more convenient operation during scaleup. Insteadof the standard Swern procedures using oxalyl chloride and DMSO inmethylene chloride at low temperatures (very exothermic reaction),sulfur trioxide-pyridine/DMSO was employed (Parikh, J., Doering, W., J.Am. Chem. Soc., 89, p. 5505, 1967) which can be conveniently performedat room temperature to give excellent yields of the desired aldehydewith high chemical and enantiomer purity which does not requirepurification.

[0048] An important reaction involves the addition of chloromethylithiumor bromomethylithium to the aldehyde. Although addition ofchloromethyllithium or bromomethylithium to aldehydes has been reportedpreviously, the addition of such species to chiral a-amino aldehydes toform chiral-aminoepoxides is believed to be novel. Now,chloromethyllithium or bromomethylithium is generated in-situ fromchloroiodomethane(or bromochloromethane) or dibromomethane andn-butyllithium at a temperature in a range from about −78° C. to about−10° C. in THF in the presence of aldehyde. The desired chlorohydrin orbromohydrin is formed as evidenced by TLC analyses. After warming toroom temperature, the desired epoxide is formed diastereoselectively ina 85:15 ratio (S:R). The product can be purified by chromatography togive the diastereomerically pure product as a colorless oil but it ismore conveniently used directly without purification.

EXAMPLE 1

[0049] β-2-[Bis(phenylmethyl)amino]benzenepropanol

[0050] Method 1:

[0051] Step 1: Benzylation of L-Phenylalanine

[0052] A solution of L-phenylalanine (50.0 g, 0.302 mol), sodiumhydroxide (24.2 g, 0.605 mol) and potassium carbonate (83.6 g, 0.605mol) in water (500 mL) was heated to 97° C. Benzyl bromide (108.5 mL,0.605 mol) was then slowly added (addition time—25 min). The mixture wasstirred at 97° C. for 30 minutes under a nitrogen atmosphere.The/solution was cooled to room temperature and extracted with toluene(2×250 mL). The combined organic layers were washed with water andbrine, dried over magnesium sulfate, filtered and concentrated to anoil. The identity of the product was confirmed as follows. AnalyticalTLC (10% ethyl acetate/hexane, silica gel) showed major component at Rfvalue=0.32 to be the desired tribenzylated compound,N,N-bis(phenylmethyl)-L-phenylalanine phenylmethyl ester. This compoundcan be purified by column chromatography (silica gel, 15% ethylacetate/hexanes). Usually the product is pure enough to be used directlyin the next step without further purification. ¹H NMR spectrum was inagreement with published literature. ¹H NMR (CDCL₃) ∂, 3.00 and 3.14(ABX-system, 2H, J_(AB)=14.1 Hz, J_(AX)=7.3 Hz and J_(BX)=5.9 Hz), 3.54and 3.92 (AB-System, 4 H, J_(AB)=13.9 Hz), 3.71 (t, 1H, J=7.6 Hz), 5.11and 5.23 (AB-System, 2H, J_(AB)=12.3 Hz), and 7.18 (m, 20 H). EIMS: m/z434 (M−1).

[0053] Step 2: βS-2-[Bis(phenylmethyl)amino]benzenepropanol from theDIBAL Reduction of N,N-bis(phenylmethyl)-L-Phenylalanine PhenylmethylEster

[0054] The benzylated phenylalanine phenylmethyl ester (0.302 mol) fromthe previous reaction was dissolved in toluene (750 mL) and cooled to−55° C. A 1.5 M solution of DIBAL in toluene (443.9 mL, 0.666 mol) wasadded at a rate to maintain the temperature between −55 to −50° C.(addition time—1 hr). The mixture was stirred for 20 minutes under anitrogen atmosphere and then quenched at −55° C. by the slow addition ofmethanol (37 ml). The cold solution was then poured into cold (5° C.)1.5 N HCl solution (1.8 L). The precipitated solid (approx. 138 g) wasfiltered off and washed with toluene. The solid material was suspendedin a mixture of toluene (400 mL) and water (100 ml). The mixture wascooled to 5° C. and treated with 2.5 N NaOH (186 mL) and then stirred atroom temperature until solid dissolved. The toluene layer was separatedfrom the aqueous phase and washed with water and brine, dried overmagnesium sulfate, filtered and concentrated to a volume of 75 mL (89g). Ethyl acetate (25 mL) and hexane (25 mL) were added to the residueupon which the desired alcohol product began to crystallize. After 30min, an additional 50 mL hexane were added to promote furthercrystallization. The solid was filtered off and washed with 50 mL hexaneto give 34.9 g of first crop product. A second crop of product (5.6 g)was isolated by refiltering the mother liquor. The two crops werecombined and recrystallized from ethyl acetate (20 mL) and hexane (30mL) to give 40 g of βS-2-[Bis(phenyl-methyl)amino]benzenepropanol, 40%yield from L-phenylalanine. An additional 7 g (7%) of product can beobtained from recrystallyzation of the concentrated mother liquor. TLCof product Rf=0.23 (10% ethyl acetate/hexane, silica gel);¹H NMR (CDCl3)∂2.44 (m, 1H,), 3.09 (m, 2H), 3.33 (m, 1H), 3.48 and 3.92 (AB-System,4H, J_(AB)=13.3 Hz), 3.52 (m, 1H) and 7.23 (m, 15H); [α]_(D)25+42.4 (c1.45, CH₂Cl₂); DSC 77.67° C.; Anal. Calcd.for C₂₃H₂₅ON: C, 83.34; H,7.60; N, 4.23. Found: C, 83.43; H, 7.59; N, 4.22. HPLC on chiralstationary phase: Cyclobond I SP column (250×4.6 mm I.D.), mobile phase:methanol/triethyl ammonium acetate buffer pH 4.2 (58:42, v/v), flow-rateof 0.5 ml/min, detection with detector at 230 nm and a temperature of 0°C. Retention time: 11.25 min., retention time of the desired productenantiomer: 12.5 min.

[0055] Method 2:

[0056] Preparation of βS-2-[Bis(phenylmethyl)amino]benzene-propanol fromthe N,N-Dibenzylation of L-Phenylalaninol:

[0057] L-phenylalaninol (176.6 g, 1.168 mol) was added to a stirredsolution of potassium carbonate (484.6 g, 3.506 mol) in 710 mL of water.The mixture was heated to 65° C. under a nitrogen atmosphere. A solutionof benzyl bromide (400 g, 2.339 mol) in 3A ethanol (305 mL) was added ata rate that maintained the temperature between 60-68° C. The biphasicsolution was stirred at 65° C. for 55 min and then allowed to cool to10° C. with vigorous stirring. The oily product solidified into smallgranules. The product was diluted with 2.0 L of tap water and stirredfor 5 minutes to dissolve the inorganic by products. The product wasisolated by filtration under reduced pressure and washed with wateruntil the pH is 7. The crude product obtained was air dried overnite togive a semi-dry solid (407 g) which was recrystallized from 1.1 L ofethyl acetate/heptane (1:10 by volume). The product was isolated byfiltration (at −8° C.), washed with 1.6 L of cold (−10° C.) ethylacetate/heptane (1:10 by volume) and air-dried to give 339 g (88% yield)of ES-2-[Bis(phenylmethyl)amino]benzene-propanol, mp 71.5-73.0° C. Moreproduct can be obtained from the mother liquor if necessary. The otheranalytical characterization was identical to compound prepared asdescribed in Method 1.

Example 2

[0058] Method 1:

[0059] αS-[Bis(phenylmethyl)amino]benzenepropanaldehyde

[0060] βS-2-[Bis(phenylmethyl)amino]benzene-propanol (200 g, 0.604 mol)was dissolved in triethylamine (300 mL, 2.15 mol). The mixture wascooled to 12° C. and a solution of sulfur trioxide/pyridine complex (380g, 2.39 mol) in DMSO (1.6 L) was added at a rate to maintain thetemperature between 8-17° C. (addition time—1.0 h). The solution wasstirred at ambient temperature under a nitrogen atmosphere for 1.5 hourat which time the reaction was complete by TLC analysis (33% ethylacetate/hexane, silica gel). The reaction mixture was cooled with icewater and quenced with 1.6 L of cold water (10-15° C.) over 45 minutes.The resultant solution was extracted with ethyl acetate (2.0 L), washedwith 5% citric acid (2.0 L), and brine (2.2 L), dried over MgSO₄ (280 g)and filtered. The solvent was removed on a rotary evaporator at 35-40°C. and then dried under vaccuum to give 198.8 g ofαS-[Bis-(phenylmethyl)amino]-benzenepropanaldehyde as a pale yellow oil(99.9%). The crude product obtained was pure enough to be used directlyin the next step without purification. The analytical data of thecompound were consistent with the published literature. [α]_(D)25=−92.9°(c 1.87, CH₂Cl₂); ¹H NMR (400 MHz, CDCl3) ∂, 2.94 and 3.15 (ABX-System,2H, J_(AB)=13.9 Hz, J_(AX)=7.3 Hz and J_(BX)=6.2 Hz), 3.56 (t, 1H, 7.1Hz), 3.69 and 3.82 (AB-System, 4H, J_(AB)=13.7 Hz), 7.25 (m, 15 H) and9.72 (s, 1H); HRMS calcd for (M+1) C₂₃H₂₄NO 330.450, found: 330.1836.Anal. Calcd. for C₂₃H₂₃ON: C, 83.86; H, 7.04; N, 4.25. Found: C, 83.64;H, 7.42; N, 4.19. HPLC on chiral stationary phase:(S,S) Pirkle-Whelk-O 1column (250×4.6 mm I.D.), mobile phase: hexane/isopropanol (99.5:0.5,v/v), flow-rate: 1.5 ml/min, detection with UV detector at 210 nm.Retention time of the desired S-isomer: 8.75 min., retention time of theR-enanatiomer 10.62 min.

[0061] Method 2:

[0062] A solution of oxalyl chloride (8.4 ml, 0.096 mol) indichloromethane (240 ml) was cooled to −74° C. A solution of DMSO (12.0ml, 0.155 mol) in dichloromethane (50 ml) was then slowly added at arate to maintain the temperature at −74° C (addition time—1.25 hr). Themixture was stirred for 5 min. followed by addition of a solution of thealcohol (0.074 mol) in 100 ml of dichloromethane (addition time—20 min.,temp. −75° C. to −68° C.). The solution was stirred at −78° C. for 35minutes under a nitrogen atmosphere. Triethylamine (41.2 ml, 0.295 mol)was then added over 10 min. (temp. −78° to −68° C.) upon which theammonium salt precipitated. The cold mixture was stirred for 30 min. andthen water (225 ml) was added. The dichloromethane layer was separatedfrom the aqueous phase and washed with water, brine, dried overmagnesium sulfate, filtered and concentrated. The residue was dilutedwith ethyl acetate and hexane and then filtered to further remove theammonium salt. The filtrate was concentrated to give the desiredaldehyde product. The aldehyde was carried on to the next step withoutpurification.

Example 3

[0063] Method 1:

[0064] N,N,αS-Tris(phenylmethyl)-2S-oxiranemethanamine

[0065] A solution of αS-[Bis(phenylmethyl)amino]benzene-propanaldehyde(191.7 g, 0.58 mol) and chloroiodomethane (56.4 mL, 0.77 mol) intetrahydrofuran (1.8 L) was cooled to −30 to −35° C. (colder temperaturesuch as −70° C. also worked well but warmer temperatures are morereadily achieved in large scale operations) in a stainless steel reactorunder a nitrogen atmosphere. A solution of n-butyllithium in hexane (1.6M, 365 mL, 0.58 mol) was then added at a rate that maintained thetemperature below −25° C. After addition the mixture was stirred at −30to −35° C. for 10 minutes. More additions of reagents were carried outin the following manner: (1) additional chloroiodomethane (17 mL) wasadded, followed by n-butyllithium (110 mL) at <−25° C. After additionthe mixture was stirred at −30 to −35° C. for 10 minutes. This wasrepeated once. (2) Additional chloroiodomethane (8.5 mL, 0.11 mol) wasadded, followed by n-butyllithium (55 mL, 0.088 mol) at <−25° C. Afteraddition the mixture was stirred at −30 to −35° C. for 10 minutes. Thiswas repeated 5 times. (3) Additional chloroiodomethane (8.5 mL, 0.11mol) was added, followed by n-butyllithium (37 mL, 0.059 mol) at <−25°C. After addition the mixture was stirred at −30 to −35° C. for 10minutes. This was repeated once. The external cooling was stopped andthe mixture warmed to ambient temp. over 4 to 16 hours when TLC (silicagel, 20% ethyl acetate/hexane) indicated that the reaction wascompleted. The reaction mixture was cooled to 10° C. and quenched with1452 g of 16% ammonium chloride solution (prepared by dissolving 232 gof ammonium chloride in 1220 mL of water), keeping the temperature below23° C. The mixture was stirred for 10 minutes and the organic andaqueous layers were separated. The aqueous phase was extracted withethyl acetate (2×500 mL). The ethyl acetate layer was combined with thetetrahydrofuran layer. The combined solution was dried over magnesiumsulfate (220 g), filtered and concentrated on a rotary evaporator at 65°C. The brown oil residue was dried at 70° C. in vacuo (0.8 bar) for 1 hto give 222.8 g of crude material. (The crude product weight was >100%.Due to the relative instability of the product on silica gel, the crudeproduct is usually used directly in the next step without purification).The diastereomeric ratio of the crude mixture was determined by protonNMR: (2S)/(2R): 86:14. The minor and major epoxide diastereomers werecharacterized in this mixture by the analysis (silica gel, 10% ethylacetate/hexane), Rf=0.29 & 0.32, respectively. An analytical sample ofeach of the diastereomers was obtained by purification on silica-gelchromatography (3% ethyl acetate/hexane) and characterized as follows:

[0066] N,N,(αS-Tris(phenylmethyl)-2S-oxiranemethanamine

[0067]¹H NMR (400 MHz, CDCl₃) ∂2.49 and 2.51 (AB-System, 1H,J_(AB)=2.82), 2.76 and 2.77 (AB-System, 1H, J_(AB)=4.03), 2.83 (m, 2H),2.99 & 3.03 (AB-System, 1H, J_(AB)=10.1 Hz), 3.15 (m, 1H), 3.73 & 3.84(AB-System, 4H, J_(AB)=14.00), 7.21 (m, 15H); ¹³C NMR (400 MHz, CDCl3) a139.55, 129.45, 128.42, 128.14, 128.09, 126.84, 125.97, 60.32, 54.23,52.13, 45.99, 33.76; HRMS calcd for C₂₄H₂₆NO (M+1) 344.477, found344.2003.

[0068] N,N,αS-Tris(phenylmethyl)-2R-oxiranemethanamine

[0069]¹H NMR (300 MHz, CDCl₃) ∂2.20 (m, 1H), 2.59 (m, 1H), 2.75 (m, 2H),2.97 (m, 1H), 3.14 (m, 1H), 3.85 (AB-System, 4H), 7.25 (m, 15H).HPLC onchiral stationary phase: Pirkle-Whelk-O 1 column (250×4.6 mm I.D.),mobile phase: hexane/isopropanol (99.5:0.5, v/v), flow-rate: 1.5 ml/min,detection with UV detector at 210 nm. Retention time of(8): 9.38 min.,retention time of enanatiomer of (4): 13.75 min.

[0070] Method 2:

[0071] A solution of the crude aldehyde 0.074 mol and chloroiodomethane(7.0 ml, 0.096 mol) in tetrahydrofuran (285 ml) was cooled to −78° C.,under a nitrogen atmosphere. A 1.6 M solution of n-butyllithium inhexane (25 ml, 0.040 mol) was then added at a rate to maintain thetemperature at −75° C. (addition time—15 min.). After the firstaddition, additional chloroiodomethane (1.6 ml, 0.022 mol) was addedagain, followed by n-butyllithium (23 ml, 0.037 mol), keeping thetemperature at −75° C. The mixture was stirred for 15 min. Each of thereagents, chloroiodomethane (0.70 ml, 0.010 mol) and n-butyllithium (5ml, 0.008 mol) were added 4 more times over 45 min. at −75° C. Thecooling bath was then removed and the solution warmed to 22° C. over 1.5hr. The mixture was poured into 300 ml of saturated aq. ammoniumchloride solution. The tetrahydrofuran layer was separated. The aqueousphase was extracted with ethyl acetate (1×300 ml). The combined organiclayers were washed with brine, dried over magnesium sulfate, filteredand concentrated to give a brown oil (27.4 g). The product could be usedin the next step without purification. The desired diastereomer can bepurified by recrystallization at a subsequent step.

[0072] The product could also be purified by chromatography.

[0073] Method 3:

[0074] A solution of αS-[Bis(phenylmethyl)amino]benzene-propanaldehyde(178.84 g, 0.54 mol) and bromochioromethane (46 mL, 0.71 mol) intetrahydrofuran (1.8 L) was cooled to −30 to −35° C. (colder temperaturesuch as −70° C. also worked well but warmer temperatures are morereadily achieved in large scale operations) in a stainless steel reactorunder a nitrogen atmosphere. A solution of n-butyllithium in hexane (1.6M, 340 mL, 0.54 mol) was then added at a rate that maintained thetemperature below −25° C. After addition the mixture was stirred at −30to −35° C. for 10 minutes. more additions of reagents were carried outin the following manner: (1) additional bromochloromethane (14 mL) wasadded, followed by n-butyllithium (102 mL) at <−25° C. After additionthe mixture was stirred at −30 to −35° C. for 10 minutes. This wasrepeated once. (2) Additional bromochloromethane (7 mL, 0.11 mol) wasadded, followed by n-butyllithium (51 mL, 0.082 mol) at <−25° C. Afteraddition the mixture was stirred at −30 to −35° C. for 10 minutes. Thiswas repeated 5 times. (3) Additional bromochloromethane (7 mL, 0.11 mol)was added, followed by n-butyllithium (51 mL, 0.082 mol) at <−25° C.After addition the mixture was stirred at −30 to −35° C. for 10 minutes.This was repeated once. The external cooling was stopped and the mixturewarmed to ambient temp. over 4 to 16 hours when TLC (silica gel, 20%ethyl acetate/hexane) indicated that the reaction was completed. Thereaction mixture was cooled to 10° C. and quenched with 1452 g of 16%ammonium chloride solution (prepared by dissolving 232 g of ammoniumchloride in 1220 mL of water), keeping the temperature below 23° C. Themixture was stirred for 10 minutes and the organic and aqueous layerswere separated. The aqueous phase was extracted with ethyl acetate(2×500 mL). The ethyl acetate layer was combined with thetetrahydrofuran layer. The combined solution was dried over magnesiumsulfate (220 g), filtered and concentrated on a rotary evaporator at 65°C. The brown oil residue was dried at 70° C. in vacuo (0.8 bar) for 1 hto give 222.8 g of crude material.

[0075] From the foregoing detailed description, one skilled in the artcan easily ascertain the essential characteristics of this invention,and without departing from the spirit and scope thereof, can makevarious changes and modifications of the invention to adapt it tovarious usages and conditions.

What is claimed is:
 1. A method of preparing an aminoepoxide compound of Formula I:

wherein P¹ and P² independently are selected from acyl, aralkyl, alkenyl, silyl, aralkoxycarbonyl, alkoxycarbonyl and cycloalkenylalkyl; wherein further P¹ and P² may be taken together with the nitrogen atom of Formula I to form a heterocyclic ring system containing said nitrogen atom as a ring member; and wherein R¹ is selected from alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl, which are optionally substituted with a group selected from alkyl, halo, NO₂, OR⁹ and SR⁹, wherein R⁹ is selected from hydrogen and alkyl; and wherein any of the foregoing groups of P¹, P² and R¹ may be substituted at one or more substitutable positions with one or more radicals independently selected from halo, alkyl of C₁-C₈, alkoxy, hydroxy, nitro, alkenyl, amino, alkylamino, acylamino and acyl; or a pharmaceutically-acceptable salt thereof; said method comprising the steps of forming a protected aminoalcohol, oxidizing said protected aminoalcohol to a chiral protected aminoaldehyde and diastereoselectively forming the aminoepoxide from said aminoaldehyde with an organometallic methylene-adding reagent in an appropriate solvent.
 2. The method of claim 1 wherein P¹ and P² independently are selected from carbobenzoxy, t-butoxycarbonyl, acetyl, butyryl, benzoyl, isobutyloxycarbonyl, allyl, 1,2-bis(dimethylsilyl)ethane, 1,2-bis(dimethylsilyl)benzene, substituted benzoyl, trifluoroacetyl, trichloroacetyl, phthaloyl, benzyl, ortho-methylbenzyl, trityl, 1,2-bis(methylene)benzene, benzhydryl, phenethyl, phenpropyl, phenyl, naphthalenyl, indenyl, anthracenyl, durenyl, 9-(9-phenyl-fluoroenyl) and phenanthrenyl, wherein further P¹ and P² may be taken together to form with the nitrogen atom of Formula I a radical selected from phthalimide, succinimide and maleimide, and wherein any of the foregoing groups of P¹ and P² may be substituted at one or more substitutable positions with one or more radicals independently selected from halo, alkyl of C₁-C₈, alkoxy, hydroxy, nitro, alkenyl, amino, alkylamino, acylamino and acyl; or a pharmaceutically-acceptable salt thereof.
 3. The method of claim 1 wherein P¹ and P² are independently selected from aralkyl, 1-2-bis(methylene)benzene and aralkyl substituted with one or more radicals independently selected from halo, alkyl of C₁-C₈, alkoxy, hydroxy, nitro, alkenyl, amino, alkylamino, acylamino and acyl; and wherein R¹ is aralkyl; or a pharmaceutically-acceptable salt thereof.
 4. A diastereoselective and enantioselective method of preparing a protected chiral alpha-amino epoxide of Formula I:

wherein P¹ and P² independently are selected from acyl, aralkyl, alkenyl, silyl, aralkoxycarbonyl, alkoxycarbonyl and cycloalkenylalkyl; wherein further P¹ and P² may be taken together with the nitrogen atom of Formula I to form a heterocyclic ring system containing said nitrogen atom as a ring member; and wherein R¹ is selected from alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl, which are optionally substituted with a group selected from alkyl, halo, NO₂, OR⁹ and SR⁹, wherein R⁹ is selected from hydrogen and alkyl; and wherein any of the foregoing groups of P¹, P² and R¹ may be substituted at one or more substitutable positions with one or more radicals independently selected from halo, alkyl of C₁-C₈, alkoxy, hydroxy, nitro, alkenyl, amino, alkylamino, acylamino and acyl; or a pharmaceutically-acceptable salt thereof; said method comprising treating a protected aminoaldehyde substrate with an organometallic methylene-adding reagent in an appropriate solvent.
 5. The method of claim 4 wherein the organometallic methylene-adding reagent is a halomethyllithium generated in situ.
 6. The method of claim 5 wherein at least an equimolar amount of organometallic methylene-adding reagent is added to the aminoaldehyde.
 7. The method of claim 4 wherein the halomethyllithium is formed through the addition of an organolithium reagent with a dihalomethane.
 8. The method of claim 4 wherein the dihalomethane is selected from bromochloromethane, chloroiodomethane, dibromomethane, diiodomethane and bromofluoromethane.
 9. The method of claim 4 wherein the halomethyllithium is added to the amino aldehyde at a temperature in a range of about −80° C. to about 0° C.
 10. The method of claim 4 wherein the halomethyllithium is added to the amino aldehyde at a temperature in a range of about −40° C. and −15° C.
 11. The diastereoselective method of preparing protected chiral alpha-amino epoxides of claim 4 wherein the amino aldehyde is alpha-S-[bis(phenylmethyl)amino]-benzenepropanaldehyde.
 12. A method of forming protected alpha-aminoaldehyde of Formula III:

wherein P¹ and P² independently are selected from acyl, aralkyl, alkenyl, silyl, aralkoxycarbonyl, alkoxycarbonyl and cycloalkenylalkyl; wherein further P¹ and P² may be taken together with the nitrogen atom of Formula III to form a heterocyclic ring system containing said nitrogen atom as a ring member; and wherein R¹ is selected from alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl, which are optionally substituted with a group selected from alkyl, halo, NO², OR⁹ and SR⁹, wherein R⁹ is selected from hydrogen and alkyl; and wherein any of the foregoing groups of P¹, P² and R¹ may be substituted at one or more substitutable positions with one or more radicals independently selected from halo, alkyl of C₁-C₈, alkoxy, hydroxy, nitro, alkenyl, amino, alkylamino, acylamino and acyl; or a pharmaceutically-acceptable salt thereof; said method comprising treating at a temperature of about 0° C. to about 30° C. a protected aminoalcohol with an oxidizing agent.
 13. The method of claim 12 wherein at least an equimolar amount of said oxidizing agent is added to the protected aminoalcohol.
 14. The method of claim 12 wherein said oxidizing agent is selected from sulfur trioxide:pyridine complex, acetyl chloride/dimethyl sulfoxide, acetyl anhydride/dimethyl sulfoxide, trifluoroacetyl chloride/dimethyl sulfoxide, toluenesulfonyl bromide/dimethyl sulfoxide, phosphorous pentachloride/dimethyl sulfoxide and isobutylchlorformate/dimethyl sulfoxide.
 15. The method of claim 12 wherein said oxidizing agent is sulfur trioxide:pyridine complex in an appropriate solvent.
 16. The method of claim 12 wherein the reaction temperature is between about 15° C. and about 30° C.
 17. The method of claim 12 wherein the protected aminoalcohol is [Bis(phenylmethyl)amino)-benzenepropanol.
 18. A method of preparing protected chiral alpha-amino alcohol of the formula:

wherein P¹ and P² independently are selected from acyl, aralkyl, alkenyl, silyl, aralkoxycarbonyl, alkoxycarbonyl and cycloalkenylalkyl; wherein further P¹ and P² may be taken together with the nitrogen atom of Formula II to form a heterocyclic ring system containing said nitrogen atom as a ring member; and wherein R¹ is selected From alkyl, aryl, cycloalkyl, cycloalkylalkyl and arylalkyl, which are optionally substituted at one or more substitutable positions with a group selected from alkyl, halo, NO₂, OR⁹ and SR⁹, wherein R⁹ is selected from hydrogen and alkyl; and wherein any of the foregoing groups of P¹, P² and R¹ may be substituted with one or more radicals independently selected from halo, alkyl of C₁-C₃, alkoxy, hydroxy, nitro, alkenyl, amino, alkylamino, acylamino and acyl; or a pharmaceutically-acceptable salt thereof; said method comprising treating said aminoalcohol with an alkylazing agent.
 19. The method of claim 18 wherein the aminoalcohol is L-phenylalaninol
 20. A method according to claim 1 characterized in that the protected chiral alpha-amino alcohol of Formula II:

as used wherein P¹, P² and R¹ are defined as indicated in claim 1 is formed by treating an amino acid with an alkylating agent to form a protected-amino acid, and forming a protected amino-alcohol by treating said protected amino acid with a reducing agent in a suitable solvent.
 21. The method of claim 20 wherein the reducing agent is diisobutylaluminum hydride.
 22. The method of claim 20 wherein said amino acid is L-phenylalanine. 